While many of us might imagine a den of sleeping bears when we hear the word dormancy, a team of scientists from Germany are quite content thinking of the various types of tissue-specific adult stem cells slumbering away. These populations of cells, including hematopoietic stem cells, normally exist in a relatively inactive state where they divide infrequently and have low energy burdens on the body.
“Our theory was that this state of dormancy protected hematopoietic stem cells from DNA damage and therefore protects them from premature aging,” said Michael Milsom, Ph.D., research group leader at the Heidelberg Institute for Stem Cell Research and Experimental Medicine and lead author on the current study.
Dr. Milsom and his team published their findings recently in Nature under an article entitled “Exit from dormancy provokes DNA-damage-induced attrition in haematopoietic stem cells”.
Under conditions of stress, such as infection or chronic blood loss, hematopoietic stem cells are forced into action, which leads to rapid cell division in order to produce new blood cells and repair damaged tissue.
“It's like forcing you out of your bed in the middle of the night and then putting you into a sports car and asking you to drive as fast as you can around a race circuit while you are still half asleep,” explained Dr. Milsom. “The stem cells go from a state of rest to very high activity within a short space of time, requiring them to rapidly increase their metabolic rate, synthesize new DNA, and coordinate cell division. Suddenly having to simultaneously execute these complicated functions dramatically increases the likelihood that something will go wrong.”
Through their research, the investigators were able to show that in times of stress, stem cells produced elevated levels of reactive metabolites that have been reported previously to directly damage DNA. While DNA repair mechanisms are present in stem cells, Dr. Milsom and his team hypothesize that continued exposure to stress increases the potential to introduce mutations due to the repair mechanisms being unable to keep up with the demand to rectify the damage. This inefficient repair would ultimately lead to cell death or toward the development of conditions such as leukemia.
“We believe that this model perfectly explains the gradual accumulation of DNA damage in stem cells with age and the associated reduction in the ability of a tissue to maintain and repair itself as you get older,” Dr. Milsom added.
Additionally, the scientists studied how the stress response impacted mice with the premature aging disorder, known to be associated with defective DNA repair, called Fanconi anemia. Patients with this disorder suffer major cardiovascular complications and are at a very high risk for developing cancer. Mouse models of Fanconi anemia have the same DNA repair defect as human patients, but the mice never spontaneously develop the bone marrow failure observed in nearly all patients.
When Fanconi anemia mice were exposed to scenario that mimicked a prolonged viral infection, they were unable to efficiently repair the resulting DNA damage, leading to stem cell failure. However, normal mice showed a gradual decline in hematopoietic stem cell numbers, while the stem cells in the Fanconi anemia mice were almost completely depleted, which ultimately led to bone marrow failure and insufficient production of blood cells to sustain life.
“This perfectly recapitulates what happens to Fanconi anemia patients and now gives us an opportunity to understand how this disease works and how we might better treat it,” concluded Dr. Milsom.